This research proposal is directed towards two related areas of central interest: 1) obtaining a greater understanding of the genetic control of the variable regions and particularly their included hypervariable portions (HV) of the immunoglobulin molecule, and 2) to define more clearly the repertoire of Ig products that may be produced by an individual lymphocyte clone during its life history of development and final expansion toward maturation. These research goals will be achieved by separate seemingly unrelated studies. 1) A comprehensive immunologic analysis of three separate pair of myeloma proteins contained in sera from individual patients. The extensive studies on these proteins includes a comparative idiotypic antigenic analysis, NH2-terminal sequence analysis of VH and VL regions, and immunofluorescent studies on donor lymphocytes to determine cellular origin of the proteins under study. 2) A study of surface Ig determinants present on tumor lymphocytes in poorly differentiated lymphocytic lymphoma which supports a hypothesis that IgD may represent the earliest Ig in ontogeny and play a key role in clonal development. As presented in this proposal, many of the studies are already in progress, and plans for completion of this work are outlined. Evidence from these investigations support strongly the notion of a V-gene switch operative in clonal Ig synthesis and as well, the concept that a single clone of cells may utilize both kappa and lambda light chains. Provocative serologic and structural data have been obtained to suggest that an IfM-lambda and IgG kappa paraproteins derived from a single sera share identical idiotypic VH determinants yet were derived from separate VH subgroups, VHI and VHIII. The genetic mechanism to account for this must await completion of the entire VH sequences.